Cells In Liver Disease Research Articles

Mesenchymal Stem Cells in Liver Diseases: Present Status and Future Perspectives.

Liver disease is a major worldwide health and economic problem. Allograft liver transplant is the only effective therapy for end-stage liver disease. The shortage of donors, the high costs, postoperative complications, and lifelong immunosuppression are rate-limiting factors for this established line of treatment. Hence, searching for therapeutic alternatives is mandatory. Stem cells are attractive candidates for cell-based therapy for their potential to support liver regeneration with few complications. They can differentiate into specialized cells, including hepatocytes to restore liver structure and function. Stem cells originating from different sources have been investigated for the treatment of liver diseases. In this review, we highlight the role of stem cells as an appropriate source for liver cell replacement in different liver diseases.

Immune regulation and therapeutic application of T regulatory cells in liver diseases.

CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.

The Roles of Myeloid-Derived Suppressor Cells in Liver Disease.

Liver disease-related mortality is a major cause of death worldwide. Hepatic innate and adaptive immune cells play diverse roles in liver homeostasis and disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells. MDSCs can be broadly divided into monocytic MDSCs and polymorphonuclear or granulocytic MDSCs, and they functionally interact with both liver parenchymal and nonparenchymal cells, such as hepatocytes and regulatory T cells, to impact liver disease progression. The infiltration and activation of MDSCs in liver disease can be regulated by inflammatory chemokines and cytokines, tumor-associated fibroblasts, epigenetic regulation factors, and gut microbiota during liver injury and cancer. Given the pivotal roles of MDSCs in advanced liver diseases, they can be targeted to treat primary and metastatic liver cancer, liver generation, alcoholic and nonalcoholic liver disease, and autoimmune hepatitis. Currently, several treatments such as the antioxidant and anti-inflammatory agent berberine are under preclinical and clinical investigation to evaluate their therapeutic efficacy on liver disease and their effect on MDSC infiltration and function. Phenotypic alteration of MDSCs in different liver diseases that are in a model-dependent manner and lack special markers for distinct MDSCs are challenges for targeting MDSCs to treat liver disease. Multi-omics study is an option to uncover the features of disease-specific MDSCs and potential gene or protein targets for liver disease treatment. In summary, MDSCs play important roles in the pathogenesis and progression of liver disease by regulating both intrahepatic innate and adaptive immune responses.

Endotheliopathy of liver sinusoidal endothelial cells in liver disease.

Liver is the largest solid organ in the abdominal cavity, with sinusoid occupying about half of its volume. Under liver disease, hemodynamics in the liver tissue dynamically change, resulting in injury to liver sinusoidal endothelial cells (LSECs). We discuss the injury of LSECs in liver diseases in this article. Generally, in noninflamed tissues, vascular endothelial cells maintain quiescence of circulating leukocytes, and unnecessary blood clotting is inhibited by multiple antithrombotic factors produced by the endothelial cells. In the setting of inflammation, injured endothelial cells lose these functions, defined as inflammatory endotheliopathy. In chronic hepatitis C, inflammatory endotheliopathy in LSECs contributes to platelet accumulation in the liver tissue, and the improvement of thrombocytopenia by splenectomy is attenuated in cases with severe hepatic inflammation. In COVID-19, LSEC endotheliopathy induced by interleukin (IL)-6 trans-signaling promotes neutrophil accumulation and platelet microthrombosis in the liver sinusoids, resulting in liver injury. IL-6 trans-signaling promotes the expression of intercellular adhesion molecule-1, chemokine (C-X-C motif) ligand (CXCL1), and CXCL2, which are the neutrophil chemotactic mediators, and P-selectin, E-selectin, and von Willebrand factor, which are involved in platelet adhesion to endothelial cells, in LSECs. Restoring LSECs function is important for ameliorating liver injury. Prevention of endotheliopathy is a potential therapeutic strategy in liver disease.

Progress in research on the role played by myeloid-derived suppressor cells in liver diseases.

Myeloid-derived suppressor cells (MDSCs) refer to a group of immature myeloid cells with potent immunosuppressive capacity upon activation by pathological conditions. Because of their potent immunosuppressive ability, MDSCs have garnered extensive attention in the past few years in the fields of oncology, infection, chronic inflammation and autoimmune diseases. Research on MDSCs in liver diseases has gradually increased, and their potential therapeutic roles will be further explored. This review presents a summary of the involvement and the role played by MDSCs in liver diseases, thus identifying their potential targets for the treatment of liver diseases and providing new directions for liver disease-related research.

γδ T cells: The potential role in liver disease and implications for cancer immunotherapy.

The γδ T cell subset was discovered over 30 years ago, yet continues to be an exciting and challenging component of the adaptive immune response. While γδ T cells represent a very small fraction of all T cells in humans, γδ T cells have a vital effect on human immunity, serving as a bridge between the innate and adaptive immune systems. The characteristics of γδ T cells include recognition of non-MHC restrictive antigens, as well as the ability to secrete an abundance of cytokines, suggesting that γδ T cells have high antitumor activity. As such, they have gained ample attention with respect to tumor immunotherapy in the last decade. The γδ T cell subset comprises up to ∼15-20% of the T-lymphocyte population in the liver, although the liver is recognized as an immune organ with primary immune functions, the role of γδ T cells in liver disease has not been established. Herein, we present a comprehensive overview of molecular mechanisms underlying immune γδ T cell activity in liver disease, including immune liver injury, viral hepatitis, cirrhosis, and hepatocellular carcinoma, and review γδ T cell-based clinical immunotherapeutic approaches.

Structural and Temporal Dynamics of Mesenchymal Stem Cells in Liver Diseases From 2001 to 2021: A Bibliometric Analysis.

BackgroundMesenchymal stem cells (MSCs) have important research value and broad application prospects in liver diseases. This study aims to comprehensively review the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in liver diseases from the perspective of bibliometrics, evaluate the clustering evolution of knowledge structure, and discover hot trends and emerging topics.MethodsThe articles and reviews related to MSCs in liver diseases were retrieved from the Web of Science Core Collection using Topic Search. A bibliometric study was performed using CiteSpace and VOSviewer.ResultsA total of 3404 articles and reviews were included over the period 2001-2021. The number of articles regarding MSCs in liver diseases showed an increasing trend. These publications mainly come from 3251 institutions in 113 countries led by China and the USA. Li L published the most papers among the publications, while Pittenger MF had the most co-citations. Analysis of the most productive journals shows that most are specialized in medical research, experimental medicine and cell biology, and cell & tissue engineering. The macroscopical sketch and micro-representation of the whole knowledge field are realized through co-citation analysis. Liver scaffold, MSC therapy, extracellular vesicle, and others are current and developing areas of the study. The keywords “machine perfusion”, “liver transplantation”, and “microRNAs” also may be the focus of new trends and future research.ConclusionsIn this study, bibliometrics and visual methods were used to review the research of MSCs in liver diseases comprehensively. This paper will help scholars better understand the dynamic evolution of the application of MSCs in liver diseases and point out the direction for future research.

Th17 cells in the liver: balancing autoimmunity and pathogen defense.

In addition to carcinogenesis, T helper 17 (Th17) cells (a subtype of CD4 + T lymphocytes) are involved in the acute, chronic, and cirrhotic phases of liver diseases; however, their role in the development and progression of liver diseases remains unclear. It is difficult to elucidate the role of Th17 cells in liver diseases due to their dichotomous nature, i.e., plasticity in terms of pathogenic or host protective function depending on environmental and time phase factors. Moreover, insufficient depletion of Th17 cells by inhibiting the cytokines and transcription factors involved in their production causes difficulties in analyzing their specific role in vitro and in vivo murine models, partially due to complex interaction. This review summarizes the recent progress in understanding the plasticity and function of hepatic Th17 cells and type 3 cytokines.

Pathogenic and Potential Therapeutic Roles of Exosomes Derived From Immune Cells in Liver Diseases.

Liver diseases, such as viral hepatitis, alcoholic hepatitis and cirrhosis, nonalcoholic steatohepatitis, and hepatocellular carcinoma place a heavy burden on many patients worldwide. However, the treatment of many liver diseases is currently insufficient, and the treatment may be associated with strong side effects. Therapies for liver diseases targeting the molecular and cellular levels that minimize adverse reactions and maximize therapeutic effects are in high demand. Immune cells are intimately involved in the occurrence, development, and prognosis of liver diseases. The immune response in the liver can be suppressed, leading to tolerance in homeostasis. When infection or tissue damage occurs, immunity in the liver is activated rapidly. As small membrane vesicles derived from diverse cells, exosomes carry multiple cargoes to exert their regulatory effects on recipient cells under physiological or pathological conditions. Exosomes from different immune cells exert different effects on liver diseases. This review describes the biology of exosomes and focuses on the effects of exosomes from different immune cells on pathogenesis, diagnosis, and prognosis and their therapeutic potential in liver diseases.

Alcohol influences gene expression and function of polymorphonuclear cells in liver disease

Background and Aim: Alcohol is one of the major causes of liver cirrhosis worldwide. Patients with alcohol-related liver diseases are highly predisposed to infection. It is reported that, neutrophils counts are higher in peripheral blood and liver tissue of these patients. Neutrophils are the first responders to infection and tissue injury and optimal neutrophil function is important in disease resolution. Thus, our objectives were to investigate the effects of alcohol on neutrophil function, gene expression and ability to resolve infection.

Current understanding of mesenchymal stem cells in liver diseases.

Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.

Emerging Importance of Chemokine Receptor CXCR4 and Its Ligand in Liver Disease.

Chemokine receptors are members of the G protein-coupled receptor superfamily, which together with chemokine ligands form chemokine networks to regulate various cellular functions, immune and physiological processes. These receptors are closely related to cell movement and thus play a vital role in several physiological and pathological processes that require regulation of cell migration. CXCR4, one of the most intensively studied chemokine receptors, is involved in many functions in addition to immune cells recruitment and plays a pivotal role in the pathogenesis of liver disease. Aberrant CXCR4 expression pattern is related to the migration and movement of liver specific cells in liver disease through its cross-talk with a variety of significant cell signaling pathways. An in-depth understanding of CXCR4-mediated signaling pathway and its role in liver disease is critical to identifying potential therapeutic strategies. Current therapeutic strategies for liver disease mainly focus on regulating the key functions of specific cells in the liver, in which the CXCR4 pathway plays a crucial role. Multiple challenges remain to be overcome in order to more effectively target CXCR4 pathway and identify novel combination therapies with existing strategies. This review emphasizes the role of CXCR4 and its important cell signaling pathways in the pathogenesis of liver disease and summarizes the targeted therapeutic studies conducted to date.

Role of liver sinusoidal endothelial cells in liver diseases.

Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia-reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.

Generation of mice with hepatocyte-specific conditional deletion of sphingosine kinase 1.

SphK1 gene has different roles in various types of cells in liver diseases, but most studies are based on global knockout mice, which hampers the study on the cellular and molecular mechanisms of SphK1. In order to further study the role of SphK1 in liver, SphK1 conditional knockout mice were constructed. A liver-specific SphK1 gene knockout mouse model was constructed by the Cre/Loxp recombinant enzyme system. PCR technologies and western blotting were used to identified the elimination of SphK1 gene in hepatocytes. SphK1flox/flox mice were used as a control group to verify the effectiveness of SphK1 liver-specific knockout mice from the profile, pathology, and serology of mice. The ablation of SphK1 in hepatic parenchymal cells was demonstrated by fluorescent in situ hybridization and the contents of S1P and Sph were measured by ELISA kit. The genotypes of liver in SphK1 conditional knockout mice were different from that of other organs. The mRNA and protein levels of SphK1 in liver tissue of SphK1 conditional knockout mice were almost depleted by compared with SphK1flox/flox mice. Physiology and pathology showed no significant difference between SphK1 liver conditional knockout mice and SphK1flox/flox mice. Additionally, SphK1 was eliminated in hepatocytes, leading to the reduce of S1P content in hepatocytes and liver tissues and the increase of Sph content in hepatocytes. The model of SphK1 gene liver conditional knockout mice was successfully constructed, providing a tool for the study of the roles of SphK1 in hepatocyte and liver diseases.

Role of γδT cells in liver diseases and its relationship with intestinal microbiota.

γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity. Based on the composition of T cell receptor and the cytokines produced, γδT cells can be divided into diverse subsets that may be present at different locations, including the liver, epithelial layer of the gut, the dermis and so on. Many of these cells perform specific functions in liver diseases, such as viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease, liver cirrhosis and liver cancers. In this review, we discuss the distribution, subsets, functions of γδT cells and the relationship between the microbiota and γδT cells in common hepatic diseases. As γδT cells have been used to cure hematological and solid tumors, we are interested in γδT cell-based immunotherapies to treat liver diseases.

The clinical application of mesenchymal stem cells in liver disease: the current situation and potential future

Liver disease is a major health issue which present poor clinical treatment performance. Cirrhosis and liver failure are common clinical manifestations of liver diseases. Liver transplantation is recognized as the ultimate and most efficient therapy to the end stage of liver disease. But it was limited by the shortage of honor organs and high cost. Nowadays, stem cell therapy gained more and more attention due to its attractive efficacy in treating liver disease especially in cirrhosis during the clinical trials. Mesenchymal stem cell (MSC) can be differentiated into hepatocytes, promote liver regeneration, inhibit liver fibrosis and induce liver apoptosis, particularly via paracrine mechanisms. This review will highlight recent clinical applications of MSC, providing the available evidence and discussing some unsolved questions in treating liver disease.

The Recruitment of Innate Immune Cells in Liver Diseases: Uncovering the Role of NK Cells and pDC in HCC and NASH

Background/ ObjectiveHepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, with over half a million new cases diagnosed annually worldwide. The fatality of HCC is high despite administration of traditional chemotherapies. In recent years, immunotherapy has become a promising strategy to treat cancer, such as PD‐1/PDL‐1 immune checkpoint blockade. However, the interactions between immune cells and HCC and how immunotherapies work, in vivo, in HCC are still unclear. Non‐alcoholic steatohepatitis (NASH) is an extremely severe form of fatty liver disease and often associated with heavy infiltration of immune cells. Natural Killer (NK) cells and plasmacytoid dendritic cells (pDC) are critical in the innate immune response, and are known for their cytotoxic and interferon producing abilities in response to cancer cells and viral pathogens, respectively. To learn more about the role of innate immunity in liver diseases, we evaluated and characterized pDC and NK cells in HCC and NASH compared to their background hepatic tissue.MethodsNK cells and pDC were isolated from HCC, NASH and hepatic tissue, stained with CD3, CD56, and CXCR6 or BDCA2 and CD123, respectively. The flow cytometry data were acquired and analyzed using FlowJo. E2‐2 immunostain for pDC was performed on FFPE tissue of HCC and NASH.ResultsThe presence of pDC was identified in the lymphoid aggregates of HCC and background cirrhotic areas (6/9 cases). In contrast, in 3 HCC cases, no pDCs were appreciated either in tumors or their backgrounds, including two patients who were smokers and with a history of coronary artery disease. In addition, using flow cytometry we demonstrated that there were more pDC in tumor infiltrating lymphocytes (TILs) of HCC compared to adjacent and distant hepatic tissues (Figure 1). We also found that NK cells isolated from NASH livers do not express CXCR6, a marker for liver‐resident NK cells, in contrast to NK cells obtained from HCC that express high levels of CXCR6 in both tumor and non‐tumor areas. The NK cells from NASH appear similar to those isolated and expanded from peripheral blood as both show low levels of CXCR6 (Figure 2). This suggests that NK cells in NASH originated from the blood and completely outnumber those in the liver, while the NK cells in HCC are residents of the liver.ConclusionsWe have shown that both pDC and NK cells are recruited to the liver in patients with NASH or HCC. More pDC were found in HCC tumors compared to surrounding hepatic tissue. NK cells isolated from NASH do not express CXCR6, a marker for liver‐resident NK cells. This study will further uncover the roles of innate immunity in liver disease and assist in the establishment of novel immunotherapies.A. pDC were present in the lymphoid aggregates of HCC and infiltrating tumor tissue.B. The numbers of pDC in TILs of HCC, adjacent and distant hepatic tissue.Figure 1Reduced expression of CXCR6 in NASH liverFigure 2

Mucosal-Associated Invariant T cell in liver diseases.

Mucosal-associated invariant T cells (MAIT cells) are a new population of innate immune cells, which are abundant in the liver and play complex roles in various liver diseases. In this review, we summarize MAIT cells in the liver diseases in recent studies, figure out the role of MAIT cells in various liver disease, including Alcoholic liver disease, Non-alcoholic liver disease, Autoimmune liver diseases, Viral hepatitis and Liver Cancer. Briefly, MAIT cells are involved in anti-bacteria responses in the alcoholic liver diseases. Besides, the activated MAIT cells promote the liver inflammation by secreting inflammatory cytokines and produce regulatory cytokines, which induces anti-inflammatory macrophage polarization. MAIT cells participate in the liver fibrosis via enhancing hepatic stellate cell activation. In viral hepatitis, MAIT cells exhibit a flawed and exhausted phenotype, which results in little effect on controlling the virus and bacteria. In liver cancer, MAIT cells indicate the disease progression and the outcome of therapy. In summary, MAIT cells are attractive biomarkers and therapeutic targets for liver disease.

Mast Cells in Liver Fibrogenesis.

Mast cells (MCs) are immune cells of the myeloid lineage that are present in the connective tissue throughout the body and in mucosa tissue. They originate from hematopoietic stem cells in the bone marrow and circulate as MC progenitors in the blood. After migration to various tissues, they differentiate into their mature form, which is characterized by a phenotype containing large granules enriched in a variety of bioactive compounds, including histamine and heparin. These cells can be activated in a receptor-dependent and -independent manner. Particularly, the activation of the high-affinity immunoglobulin E (IgE) receptor, also known as FcεRI, that is expressed on the surface of MCs provoke specific signaling cascades that leads to intracellular calcium influx, activation of different transcription factors, degranulation, and cytokine production. Therefore, MCs modulate many aspects in physiological and pathological conditions, including wound healing, defense against pathogens, immune tolerance, allergy, anaphylaxis, autoimmune defects, inflammation, and infectious and other disorders. In the liver, MCs are mainly associated with connective tissue located in the surrounding of the hepatic arteries, veins, and bile ducts. Recent work has demonstrated a significant increase in MC number during hepatic injury, suggesting an important role of these cells in liver disease and progression. In the present review, we summarize aspects of MC function and mediators in experimental liver injury, their interaction with other hepatic cell types, and their contribution to the pathogenesis of fibrosis.

Pre-treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases.

Liver diseases caused by viral infection, alcohol abuse and metabolic disorders can progress to end‐stage liver failure, liver cirrhosis and liver cancer, which are a growing cause of death worldwide. Although liver transplantation and hepatocyte transplantation are useful strategies to promote liver regeneration, they are limited by scarce sources of organs and hepatocytes. Mesenchymal stem cells (MSCs) restore liver injury after hepatogenic differentiation and exert immunomodulatory, anti‐inflammatory, antifibrotic, antioxidative stress and antiapoptotic effects on liver cells in vivo. After isolation and culture in vitro, MSCs are faced with nutrient and oxygen deprivation, and external growth factors maintain MSC capacities for further applications. In addition, MSCs are placed in a harsh microenvironment, and anoikis and inflammation after transplantation in vivo significantly decrease their regenerative capacity. Pre‐treatment with chemical agents, hypoxia, an inflammatory microenvironment and gene modification can protect MSCs against injury, and pre‐treated MSCs show improved hepatogenic differentiation, homing capacity, survival and paracrine effects in vitro and in vivo in regard to attenuating liver injury. In this review, we mainly focus on pre‐treatments and the underlying mechanisms for improving the therapeutic effects of MSCs in various liver diseases. Thus, we provide evidence for the development of MSC‐based cell therapy to prevent acute or chronic liver injury. Mesenchymal stem cells have potential as a therapeutic to prolong the survival of patients with end‐stage liver diseases in the near future.